Pharmacokinetics and Pharmacodynamics of Midazolam and Metabolites in Nonventilated Infants after Craniofacial Surgery

2006 ◽  
Vol 105 (6) ◽  
pp. 1135-1146 ◽  
Author(s):  
Mariska Y. M. Peeters ◽  
Sandra A. Prins ◽  
Catherijne A. J. Knibbe ◽  
Joost DeJongh ◽  
Ron A. A. Mathôt ◽  
...  
Keyword(s):  
Bispectral Index ◽  
Interindividual Variability ◽  
Initial Dosage ◽  
Optimal Dose ◽  
Volume Of Distribution ◽  
Pharmacodynamic Modeling ◽  
Major Surgery ◽  
Maximum Effect ◽  
Population Pharmacokinetic ◽  
Emax Model

Background Because information on the optimal dose of midazolam for sedation of nonventilated infants after major surgery is scant, a population pharmacokinetic and pharmacodynamic model is developed for this specific group. Methods Twenty-four of the 53 evaluated infants (aged 3-24 months) admitted to the Pediatric Surgery Intensive Care Unit, who required sedation judged necessary on the basis of the COMFORT-Behavior score and were randomly assigned to receive midazolam, were included in the analysis. Bispectral Index values were recorded concordantly. Population pharmacokinetic and pharmacodynamic modeling was performed using NONMEM V (GloboMax LLC, Hanover, MD). Results For midazolam, total clearance was 0.157 l/min, central volume was 3.8 l, peripheral volume was 30.2 l, and intercompartmental clearance was 0.30 l/min. Assuming 60% conversion of midazolam to 1-OH-midazolam, the volume of distribution for 1-OH-midazolam and 1-OH-midazolamglucuronide was 6.7 and 1.7 l, and clearance was 0.21 and 0.047 l/min, respectively. Depth of sedation using COMFORT-Behavior could adequately be described by a baseline, postanesthesia effect (Emax model) and midazolam effect (Emax model).The midazolam concentration at half maximum effect was 0.58 mum with a high interindividual variability of 89%. Using the Bispectral Index, in 57% of the infants the effect of midazolam could not be characterized. Conclusion In nonventilated infants after major surgery, midazolam clearance is two to five times higher than in ventilated children. From the model presented, the recommended initial dosage is a loading dose of 1 mg followed by a continuous infusion of 0.5 mg/h during the night for a COMFORT-Behavior of 12-14 in infants aged 1 yr. Large interindividual variability warrants individual titration of midazolam in these children.

Propofol Pharmacokinetics and Pharmacodynamics for Depth of Sedation in Nonventilated Infants after Major Craniofacial Surgery

2006 ◽  
Vol 104 (3) ◽  
pp. 466-474 ◽  
Author(s):  
Mariska Y. M. Peeters ◽  
Sandra A. Prins ◽  
Catherijne A. J. Knibbe ◽  
Joost DeJongh ◽  
Ron H. N. van Schaik ◽  
...  
Keyword(s):  
Bispectral Index ◽  
Coefficient Of Variation ◽  
Craniofacial Surgery ◽  
Dose Titration ◽  
Maximum Effect ◽  
Population Pharmacokinetic ◽  
Healthy Children ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Emax Model ◽  
Behavior Scale

Background To support safe and effective use of propofol in nonventilated children after major surgery, a model for propofol pharmacokinetics and pharmacodynamics is described. Methods After craniofacial surgery, 22 of the 44 evaluated infants (aged 3-17 months) in the pediatric intensive care unit received propofol (2-4 mg . kg-1 . h-1) during a median of 12.5 h, based on the COMFORT-Behavior score. COMFORT-Behavior scores and Bispectral Index values were recorded simultaneously. Population pharmacokinetic and pharmacodynamic modeling was performed using NONMEM V (GloboMax LLC, Hanover, MD). Results In the two-compartment model, body weight (median, 8.9 kg) was a significant covariate. Typical values were Cl = 0.70 . (BW/8.9)0.61 l/min, Vc = 18.8 l, Q = 0.35 l/min, and Vss = 146 l. In infants who received no sedative, depth of sedation was a function of baseline, postanesthesia effect (Emax model), and circadian night rhythm. In agitated infants, depth of sedation was best described by baseline, postanesthesia effect, and propofol effect (Emax model). The propofol concentration at half maximum effect was 1.76 mg/l (coefficient of variation = 47%) for the COMFORT-Behavior scale and 3.71 mg/l (coefficient of variation = 145%) for the Bispectral Index. Conclusions Propofol clearance is two times higher in nonventilated healthy children than reported in the literature for ventilated children and adults. Based on the model, the authors advise a propofol dose of 30 mg/h in a 10-kg infant to achieve values of 12-14 on the COMFORT-Behavior scale and 70-75 on the Bispectral Index during the night. Wide pharmacodynamic variability emphasizes the importance of dose titration.

Phase I and pharmacokinetic study of the water-soluble dolastatin 15 analog LU103793 in patients with advanced solid malignancies.

1998 ◽  
Vol 16 (8) ◽  
pp. 2770-2779 ◽  
Author(s):  
M A Villalona-Calero ◽  
S D Baker ◽  
L Hammond ◽  
C Aylesworth ◽  
S G Eckhardt ◽  
...  
Keyword(s):  
Cardiovascular Effects ◽  
Pharmacokinetic Profile ◽  
Maximum Tolerated Dose ◽  
Volume Of Distribution ◽  
Water Soluble ◽  
Maximum Effect ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
Emax Model ◽  
Solid Malignancies

PURPOSE To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic profile of the dolastatin 15 analog LU103793 when administered daily for 5 days every 3 weeks. PATIENTS AND METHODS Fifty-six courses of LU103793 at doses of 0.5 to 3.0 mg/m2 were administered to 26 patients with advanced solid malignancies. Pharmacokinetic studies were performed on days 1 and 5 of course one. Pharmacokinetic variables were related to the principal toxicities. RESULTS Neutropenia, peripheral edema, and liver function test abnormalities were dose-limiting at doses greater than 2.5 mg/m2 per day. Four of six patients developed DLT at 3.0 mg/m2 per day, whereas two of 12 patients treated at 2.5 mg/m2 per day developed DLT. Pharmacokinetic parameters were independent of dose and similar on days 1 and 5. Volume of distribution at steady-state (Vss) was 7.6 +/- 2.0 L/m2, clearance 0.49 +/- 0.18 L/h/m2, and elimination half-life (t1/2) 12.3 +/- 3.8 hours. Peak concentrations (Cmax) on day 1 related to mean percentage decrement in neutrophils (sigmoid maximum effect (Emax) model). Patients who experienced dose-limiting neutropenia had significantly higher Cmax values than patients who did not, whereas nonhematologic DLTs were more related to dose. CONCLUSION The recommended dose for phase II evaluations of LU103793 daily for 5 days every 3 weeks is 2.5 mg/m2 per day. The lack of prohibitive cardiovascular effects and the generally acceptable toxicity profile support the rationale for performing disease-directed evaluations of LU103793 on the schedule evaluated in this study.

Population Pharmacokinetic‐Pharmacodynamic Modeling for Propofol Anesthesia Guided by the Bispectral Index (BIS)

2019 ◽  
Author(s):  
Ana Maria Araújo ◽  
Humberto Machado ◽  
Paula Guedes Pinho ◽  
Patrício Soares‐da‐Silva ◽  
Amílcar Falcão
Keyword(s):  
Bispectral Index ◽  
Pharmacodynamic Modeling ◽  
Population Pharmacokinetic

scholarly journals Modeling and Simulation of Pretomanid Pharmacokinetics in Pulmonary Tuberculosis Patients

2018 ◽  
Vol 62 (7) ◽  
pp. e02359-17 ◽  
Author(s):  
Michael A. Lyons
Keyword(s):  
Geometric Mean ◽  
Late Phase ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Maximum Effect ◽  
Population Pharmacokinetic ◽  
Clinical Testing ◽  
Half Maximum ◽  
Two Phase ◽  
Fed State

ABSTRACTPretomanid is a nitroimidazole antibiotic in late-phase clinical testing as a component of several novel antituberculosis (anti-TB) regimens. A population pharmacokinetic model for pretomanid was constructed using a Bayesian analysis of data from two phase 2 studies, PA-824-CL-007 and PA-824-CL-010, conducted with adult (median age, 27 years) patients in Cape Town, South Africa, with newly diagnosed pulmonary TB. Combined, these studies included 63 males and 59 females administered once-daily oral pretomanid doses of 50, 100, 150, 200, 600, 1,000, or 1,200 mg for 14 days. The observed pretomanid plasma concentration-time profiles for all tested doses were described by a one-compartment model with first-order absorption and elimination and a sigmoidal bioavailability dependent on dose, time, and the predose fed state. Allometric scaling with body weight (normalized to 70 kg) was used for volume of distribution and clearance, with the scaling exponents equal to 1 and 3/4, respectively. The posterior population geometric means for the clearance and volume of distribution allometric constants were 4.8 ± 0.2 liters/h and 130 ± 5 liters, respectively, and the posterior population geometric mean for the half-maximum-effect dose for the reduction of bioavailability was 450 ± 50 mg. Interindividual variability, described by the percent coefficient of variation, was 32% ± 3% for clearance, 17% ± 4% for the volume of distribution, and 74% ± 9% for the half-maximum-effect dose. This model provides a dose-exposure relationship for pretomanid in adult TB patients with potential applications to dose selection in individuals and to further clinical testing of novel pretomanid-containing anti-TB regimens.

scholarly journals Population Pharmacokinetics and Dose Optimization of Ceftazidime and Imipenem in Patients with Acute Exacerbations of Chronic Obstructive Pulmonary Disease

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 456
Author(s):  
Thu-Minh Nguyen ◽  
Thu-Hue Ngo ◽  
Anh-Quan Truong ◽  
Dinh-Hoa Vu ◽  
Dinh-Chi Le ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Optimal Dose ◽  
Volume Of Distribution ◽  
Chronic Obstructive ◽  
Population Pharmacokinetic ◽  
Obstructive Pulmonary Disease ◽  
Dosing Algorithm ◽  
Acute Exacerbations ◽  
Optimal Regimen

Background: Ceftazidime and imipenem have been increasingly used to treat Acute Exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD) due to their extended-spectrum covering Pseudomonas aeruginosa. This study aims to describe the population pharmacokinetic (PK) and pharmacodynamic (PD) target attainment for ceftazidime and imipenem in patients with AECOPD. Methods: We conducted a prospective PK study at Bach Mai Hospital (Viet Nam). A total of 50 (ceftazidime) and 44 (imipenem) patients with AECOPD were enrolled. Population PK analysis was performed using Monolix 2019R1 and Monte Carlo simulations were conducted to determine the optimal dose regimen with respect to the attainment of 60% and 40% fT>MIC for ceftazidime and imipenem, respectively. A dosing algorithm was developed to identify optimal treatment doses. Results: Ceftazidime and imipenem PK was best described by a one-compartment population model with a volume of distribution and clearance of 23.7 L and 8.74 L/h for ceftazidime and 15.1 L and 7.88 L/h for imipenem, respectively. Cockcroft–Gault creatinine clearance represented a significant covariate affecting the clearance of both drugs. Increased doses with prolonged infusion were found to cover pathogens with reduced susceptibility. Conclusions: This study describes a novel and versatile three-level dosing algorithm based on patients’ renal function and characteristic of the infective pathogen to explore ceftazidime and imipenem optimal regimen for AECOPD.

A combined pharmacometric analysis of dabigatran etexilate in healthy volunteers and patients with atrial fibrillation or undergoing orthopaedic surgery

2012 ◽  
Vol 107 (04) ◽  
pp. 775-785 ◽  
Author(s):  
Thorsten Lehr ◽  
Karl-Heinz Liesenfeld ◽  
Sebastian Haertter ◽  
Alexander Staab ◽  
Chantaratsamon Dansirikul
Keyword(s):  
Atrial Fibrillation ◽  
Healthy Volunteers ◽  
Orthopaedic Surgery ◽  
Dabigatran Etexilate ◽  
Plasma Concentrations ◽  
Thrombin Inhibitor ◽  
Maximum Effect ◽  
Population Pharmacokinetic ◽  
Emax Model ◽  
Orally Bioavailable

SummaryDabigatran etexilate is the orally bioavailable pro-drug of dabigatran, a direct thrombin inhibitor. Using data from eight clinical studies in healthy volunteers and patients with non-valvular atrial fibrillation (AF) or undergoing orthopaedic surgery (OS), population pharmacokinetic (PK) and pharmacodynamic (PD) models were developed to investigate whether the PK and PD of dabigatran differ across different populations. In both healthy volunteers (n=80) and patients (n=1,965), the PK of dabigatran was best described by a two-compartment disposition model with first-order absorption and elimination. Renal function was the only covariate shown to have a clinically relevant impact on dabig-atran exposure. The patient PK model was successfully applied in predicting exposure observed in the RE-LY trial evaluating dabigatran treatment in patients with non-valvular AF. The relationship between dabigatran plasma concentrations and activated partial thromboplastin time in healthy volunteers and patients (n=762) was best described with a combination of a linear model and a maximum effect (Emax) model, consistent with previous reports. PK/PD relationships were robust across the various populations tested and were not affected by any of the covariates examined. In summary, the PK of dabigatran is sufficiently consistent to allow extrapolation of data generated in healthy volunteers to patients with AF or undergoing OS.

scholarly journals Model-informed precision dosing for alemtuzumab in pediatric and young adult patients undergoing allogeneic hematopoietic cell transplantation

2021 ◽  
Author(s):  
Min Dong ◽  
Chie Emoto ◽  
Tsuyoshi Fukuda ◽  
Danielle Arnold ◽  
Parinda Mehta ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Absolute Lymphocyte Count ◽  
Compartment Model ◽  
Optimal Level ◽  
Volume Of Distribution ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Population Pharmacokinetic ◽  
Emax Model

Aim: Alemtuzumab is a lymphodepleting monoclonal antibody utilized in conditioning regimens for allogeneic hematopoietic cell transplantation (HCT). A therapeutic range of 0.15-0.6 µg/mL on the day of transplantation is associated with better HCT outcomes. The purpose of this study was to characterize alemtuzumab population pharmacokinetic/pharmacodynamic (PK/PD) and to propose individualized subcutaneous dosing schemes to achieve this optimal level for pediatric patients. Methods: Alemtuzumab concentration and absolute lymphocyte count (ALC) profiles were obtained from 29 patients with non-malignant disorders undergoing HCT. PK/ PD analyses were performed using non-linear mixed effects modeling. Monte Carlo simulation was conducted to evaluate different improved dosing approaches. Results: A one-compartment model with sequential zero- and first-order absorption adequately described subcutaneously administered alemtuzumab PK. Model fit was significantly improved by including allometrically scaled body weight on clearance (0.080 L/h/70kg) and volume of distribution (17.4 L/70kg). ALC reduction following subcutaneous alemtuzumab was swift. An inhibitory Emax model best characterized the relationship between alemtuzumab concentration and ALC. Emax and EC50 were estimated as 1.18*103/µL and 0.045µg/mL, respectively. The currently used per kg dosing was found to cause uneven alemtuzumab exposure across different age and weight cohorts. Simulations indicated target achieving dose as allometry-based of 18 mg*(weight/70)0.75 or body surface area (BSA)-based of 10 mg/m2, divided over 3 days, with a potential individualized top-up dose; both of which yielded similar results. Conclusion: An allometry- or BSA-based starting dosing regimen in combination with individualized Bayesian PK estimation using concentration feedback is proposed for alemtuzumab precision dosing in children undergoing allogeneic HCT.

Population Pharmacokinetic of Native Escherichia Coli Asparaginase.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4803-4803
Author(s):  
Stephan Borghorst ◽  
Rob Pieters ◽  
Hans Juergen Kuehnel ◽  
Joachim Boos ◽  
Georg Hempel
Keyword(s):  
Escherichia Coli ◽  
Interindividual Variability ◽  
Treatment Protocol ◽  
Volume Of Distribution ◽  
Face Validity ◽  
Pharmacokinetic Parameters ◽  
Population Pharmacokinetic ◽  
Published Data ◽  
Pharmacokinetic Data ◽  
Poppk Model

Abstract Abstract 4803 Introduction Native Escherichia Coli Asparaginase (ASNase) is an integral component in the therapy of acute lymphoblastic leukemia (ALL) and non-Hodgkin's Lymphoma (NHL). There is a great interindividual variability in treatment intensity in patients treated with the same dose of ASNase. Population pharmacokinetics (PopPK) provides the possibility to divide the overall variability of a population in an inter- and intraindividual element and to develop more precise dosing recommendations. Furthermore, pharmacokinetic parameters can be estimated as well as possible covariates that may influence the pharmacokinetics of the drug can be identified. Patients and Methods The model building dataset consisted of 16 patients (233 samples) receiving 5000 U/m2 ASNase (Asparaginase Medac®) 8 times according to the DCOG-ALL 10 treatment protocol. Asparaginase activity was measured in a randomized clinical Phase 2 study comparing the pharmacokinetic and pharmacodynamic of a newly developed recombinant ASNase with that of the established ASNase (Asparaginase Medac®)[R. Pieters et al. Blood. 2008 Dec 15. 112(13):4832-8]. The PopPK-model was developed using NONMEM (version VI) with First Order Conditional Estimation (FOCE) method and INTERACTION option. Results A linear 2-compartmental model with a combined proportional (0.9%) and additive (48.1U/l) error model described the data adequately. The pharmacokinetic parameters estimated were: Total systemic clearance 0.135 ± 12.8% l/h/70kg, volume of distribution of the central compartment 4.27 ± 13.1% l/70kg, volume of distribution in the peripheral compartment 0.83 ± 80.4% l/70kg and intercompartmental clearance 0.058 l/h/70kg (mean ± interindividual variability). Body weight was identified as the most important covariate. Validity of the model was verified by simulating different dosages of ASNase (2500U/m2 and 10000U/m2) in induction and reinduction of the ALL-BFM treatment protocol. The median and mean ASNase activity was compared with published data [E. Ahlke et al. Br J Haematol. 1997 Mar. 96(4):675-81 and Boos et al. Eur J Cancer. 1996 Aug. 32A(9):1544-50]. Furthermore pharmacokinetic data obtained by a noncompartmental analysis [R. Pieters et al. Blood. 2008 Dec 15.112(13):4832-8] were compared with the pharmacokinetic data estimated by the PopPK model. Both procedures indicated on face validity of the PopPK model. Conclusion This PopPK analysis provides the first step in the development of a PopPK model for ASNase. Face validity of the PopPK model could be demonstrated and will be confirmed with an independent dataset. Disclosures: Pieters: Medac GmbH: Research Funding. Kuehnel:Medac GmbH: Employment. Boos:Medac GmbH: Honoraria. Hempel:Medac GmbH: Honoraria.

scholarly journals Pharmacodynamic modeling of the in vivo interaction between cefotaxime and ofloxacin by using serum ultrafiltrate inhibitory titers.

1997 ◽  
Vol 41 (5) ◽  
pp. 1108-1114 ◽  
Author(s):  
D E Nix ◽  
J H Wilton ◽  
J Hyatt ◽  
J Thomas ◽  
L C Strenkoski-Nix ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Volume Of Distribution ◽  
Pharmacodynamic Modeling ◽  
Emax Model ◽  
Test Organisms ◽  
Total Body ◽  
Randomized Crossover Study ◽  
Sigmoid Emax Model

The pharmacokinetics (PK) and pharmacodynamics (PD) of cefotaxime and ofloxacin and of their combination were examined in a three-period randomized crossover study involving 12 healthy adults. The PK of cefotaxime and ofloxacin were modeled. PD was assessed from the predicted concentrations in serum and serum untrafiltrate inhibitory titers for 10 test organisms. An inhibitory sigmoid Emax model based on the probability of bacterial growth was used, where Emax = 1 and EC50 is the concentration resulting in a 50% probability of growth. The total body clearance (CL(T)) and volume of distribution at steady state (V(SS)) for cefotaxime were 0.236 liters/kg/h and 0.207 liters/kg, respectively, for the monotherapy and 0.231 liters/kg/h and 0.208 liters/kg for the combination therapy. Ofloxacin exhibited PK parameters of 0.143 liters/kg/h for CL(T) and 1.20 liters/kg for V(SS) following the monotherapy and of 0.141 liters/kg/h for CL(T) and 1.16 liters/kg for V(SS) following combination therapy. For the combination therapy, an interaction term, theta, defined the type and relative extent of interaction. The range of observed theta values (-0.033 to 0.067) is consistent with an additive PD interaction according to standards similar to those used for the in vitro fractional inhibitory concentration index.

Population pharmacokinetic and pharmacodynamic modeling of epinephrine administered using a mobile inhaler

2015 ◽  
Vol 30 (6) ◽  
pp. 391-399 ◽  
Author(s):  
Sebastian Frechen ◽  
Ahmed Abbas Suleiman ◽  
Ali Mohammad Nejad Sigaroudi ◽  
Bertil Wachall ◽  
Uwe Fuhr
Keyword(s):  
Pharmacodynamic Modeling ◽  
Population Pharmacokinetic
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